Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death
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Daniela Catanzaro1, Edoardo Gaude2, Genny Orso3, Carla Giordano4, Giulia Guzzo5, Andrea Rasola5, Eugenio Ragazzi1, Laura Caparrotta1, Christian Frezza2, Monica Montopoli1
1Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
2MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK
3IRCCS “E. Medea”, Conegliano, Italy
4Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Roma, Italy
5Department of Biomedical Sciences, University of Padova, Padova, Italy
Christian Frezza, e-mail: firstname.lastname@example.org
Monica Montopoli, e-mail: email@example.com
Keywords: cisplatin, drug resistance, cancer metabolism, PPP, transmitochondrial hybrids
Received: March 22, 2015 Accepted: August 07, 2015 Published: August 17, 2015
The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.
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